Liquid Lipids Act as Polymorphic Modifiers of Tristearin-Based Formulations Produced by Melting Technologies

Despite the growing interest in lipid-based formulations, their polymorphism is still a challenge in the pharmaceutical industry. Understanding and controlling the polymorphic behavior of lipids is a key element for achieving the quality and preventing stability issues. This study aims to evaluate the impact of different oral-approved liquid lipids (LL) on the polymorphism, phase transitions and structure of solid lipid-based formulations and explore their influence on drug release. The LL investigated were isopropyl myristate, ethyl oleate, oleic acid, medium chain trigycerides, vitamin E acetate, glyceryl monooleate, lecithin and sorbitane monooleate. Spray-congealing was selected as an example of a melting-based solvent-free manufacturing method to produce microparticles (MPs) of tristearin (Dynasan(R)118). During the production process, tristearin MPs crystallized in the metastable alpha-form. Stability studied evidenced a slow phase transition to the stable beta-polymorph overtime, with the presence of the alpha-form still detected after 60 days of storage at 25 degrees C. The addition of 10% w/w of LL promoted the transition of tristearin from the alpha-form to the stable beta-form with a kinetic varying from few minutes to days, depending on the specific LL. The combination of various techniques (DSC, X-ray diffraction analysis, Hot-stage polarized light microscopy, SEM) showed that the addition of LL significantly modified the crystal structure of tristearin-based formulations at different length scales. Both the polymorphic form and the LL addition had a strong influence on the release behavior of a model hydrophilic drug (caffeine). Overall, the addition of LL can be considered an interesting approach to control triglyceride crystallization in the beta-form. From the industrial viewpoint, this approach might be advantageous as any polymorphic change will be complete before storage, hence enabling the production of stable lipid formulations.

Automated summary

This study evaluated the impact of different oral-approved liquid lipids on the polymorphism, phase transitions, and structure of solid lipid-based formulations, and their influence on drug release. The addition of liquid lipids was found to promote the transition of tristearin from the alpha-form to the stable beta-form, affecting the crystal structure of tristearin-based formulations and influencing the release behavior of a model hydrophilic drug. Overall, the addition of liquid lipids can be considered an interesting approach to control triglyceride crystallization in the beta-form, enabling the production of stable lipid formulations.